Spontaneous Hepatitis B E Antigen Seroconversion Research Articles

Insights into the Natural and Treatment Courses of Hepatitis B in Children: A Retrospective Study.

Chronic Hepatitis B virus (HBV) infection in children remains a significant public health challenge. The natural history and treatment outcomes of HBV can vary widely, influencing management strategies. This retrospective study was conducted in Northeast Romania and involved a cohort of 148 pediatric patients diagnosed with chronic viral Hepatitis B. Of these, 59 children underwent antiviral treatment while 89 were not treated. One of the main objectives was the rate of HBeAg (Hepatitis B-e antigen) seroconversion, a marker of disease progression and response to therapy. Among the treated group, 26 children (44%) achieved HBeAg seroconversion following therapy. In contrast, 44 of the untreated children (49%) experienced spontaneous HBeAg seroconversion, indicating a substantial rate of natural resolution within this population subset. The findings highlight a significant proportion of spontaneous seroconversion in untreated pediatric patients, suggesting a potential re-evaluation of treatment criteria and timing for children with chronic HBV infection. The comparable rates of seroconversion between treated and untreated cohorts underscore the need for individualized treatment approaches based on a combination of virological, biochemical, and clinical parameters. Further studies are required to refine management strategies to optimize long-term outcomes in pediatric HBV infections.

Genetic variants of NTCP gene and hepatitis B vaccine failure in Taiwanese children of hepatitis B e antigen positive mothers.

Hepatitis B virus (HBV) vaccine failure remains a hurdle to the global elimination of HBV infections in the vaccination era. We aimed to elucidate the relationships between HBV entry receptor sodium taurocholate co-transporting polypeptide (NTCP) and vaccine failure in children born to highly infectious mothers. The genetic variants rs7154439, rs4646285, rs4646287, and rs2296651 were genotyped in 170 children with chronic HBV infections and 138 control children of mothers positive for hepatitis B e antigen (HBeAg). All children received hepatitis B immunoglobulin and complete HBV vaccination. Total RNAs from 82 adult non-tumor liver tissues were quantified for NTCP, type I interferons and interferon-induced transmembrane protein 3 (IFITM3) levels. A higher rate of the GA/AA genotype (28.3% vs. 15.3%, p = 0.006) of the genetic variant rs4646287 in intron 1 of the NTCP gene was detected in control children compared to the carrier children. The rs4646287 G > A genotype was associated with younger ages at which spontaneous HBeAg seroconversion occurred (10.8 ± 8.4 vs. 14.6 ± 8.7years, p = 0.003) in chronic HBV-infected children. Unique correlation patterns of NTCP and innate immunity-related genes (type I interferons and IFITM3) were found in HBV-infected liver tissues with the rs4646287 G > A genotype. The rs4646287 G > A genotype of the NTCP gene may be associated with lower risk for HBV vaccine failure in children born to highly infectious mothers. The protective effect of rs4646287 G > A was also present in carrier children, evidenced by earlier spontaneous HBeAg seroconversion.

Combining the HBcrAg decline and HBV mutations predicts spontaneous HBeAg seroconversion in chronic hepatitis B patients during the immune clearance phase.

To assess predictive ability of hepatitis B virus (HBV) markers and genome mutations for spontaneous hepatitis B e antigen (HBeAg) seroconversion. A total of 113 chronic hepatitis B (CHB) patients were followed up for 76 weeks without antiviral treatment. Baseline basal core promoter (BCP) and precore mutations were detected and serum hepatitis B surface antigen (HBsAg), HBeAg, hepatitis B core-related antigen (HBcrAg), and HBV DNA levels were serially quantified. Eighteen patients experienced spontaneous HBeAg seroconversion (Group A), and the remaining 95 patients did not experience spontaneous HBeAg seroconversion (Group B). At Week 28, HBsAg (p = 0.03) and HBcrAg (p = 0.01) levels were significantly different between Groups A and B. Reduced HBsAg (p = 0.02) and HBcrAg (p < 0.01) levels from baseline to Week 28 were significantly different between two groups. Multivariate logistic regression showed that lower HBcrAg (odds ratio [OR] = 1.02, p = 0.03) levels at Week 28, and HBcrAg levels with sharp decrease at Week 28 (OR = 0.19, p = 0.02) were related with spontaneous HBeAg seroconversion. The areas under the receiver operating characteristic curve (AUROC) showed that reduction in HBcrAg levels from baseline to Week 28 (0.93, p = 0.001, 95% CI: 0.74-1.08) have excellent prediction value. The mutation frequencies of A1574T (51.11% vs. 18.18%, p = 0.001), G1862A (30.00% vs. 13.03%, p = 0.001), G1896A (27.22% vs. 5.45%, p = 0.001), and C1913G (32.78% vs. 12.73%, p = 0.001) in Group A were significantly higher than Group B. Baseline A1574T, G1862A, G1896A, and C1913G mutations and HBcrAg levels with a sharp decrease at Week 28 were associated with spontaneous HBeAg seroconversion.

Real-world efficacy of immunoprophylaxis against mother-to-infant transmission of hepatitis B virus based on puerperant population

Objective To assess the efficacy of immunoprophylaxis against mother-to-infant transmission of hepatitis B virus (HBV) in a real-world setting since the implementation of charge-free hepatitis B immunoglobulin (HBIG) and hepatitis B vaccine in China. Methods The screening rate and the prevalence of hepatitis B surface antigen (HBsAg) in 61 790 puerperants, and the administration of combined immunoprophylaxis in infants of HBsAg-positive mothers in Rugao City of Jiangsu Province from July 1, 2011 to June 30, 2016 were retrospectively analyzed. HBV infection status of infants born to HBV infected mothers was followed up after 7 months of age. HBsAg-positive infants and their mothers were followed up again for HBV markers in April 2018. Fisher's exact test and Cochran-Armitage trend test were used to statistically analyze the differences between groups and various years, respectively. Results All 61 790 puerperants were screened for HBsAg and the prenatal screen rate was 98.6% (60 937/61 790) with an increasing trend over time (χ2trend=750.908, P<0.001). HBsAg-positive puerperants accounted for 5.5% (3 397/61 790) with a decreasing trend over time (χ2trend=32.667, P<0.001). In total, 778 offspring (399 boys and 379 girls) of 759 HBsAg-positive mothers were followed up at (13.7±6.9) months of age, among which 751 (96.5%) were administered and 25 (3.2%) were probably administered standard combined immunoprophylaxis after birth, and the rest two (0.3%) were not. Fourteen infants (1.8%) were HBsAg positive and all born to mothers with positive hepatitis B e antigen (HBeAg). None of the 538 infants born to HBeAg-negative mothers was HBsAg-positive. HBsAg-positive rate in infants born since 2013 was lower than those in 2011 and 2012 (χ2trend=13.352, P=0.000 3). Eleven HBsAg-positive mothers and their children were followed up again 4–5 years later in April 2018. HBV DNA levels of all mothers were within the range of (7.34–28.2)×107 IU/ml except one case of spontaneous HBeAg seroconversion. One out of the 11 infected children also had HBeAg seroconversion. Phylogenetic analysis of HBV S gene showed that the 11 pairs of mothers and children were all infected with HBV of genotype C. Conclusions The implementation of charge-free HBIG and hepatitis B vaccine for newborns achieves fruitful results in Rugao city as the mother-to-infant transmission of HBV in the real-world had been further reduced to a similar level reported in literature survey. Key words: Hepatitis B virus; Hepatitis B; Infectious disease transmission, vertical; Immunoglobulins; Communicable disease control

Baseline Level of Hepatitis B Core Antibody Predicts Spontaneous Hepatitis B e Antigen (HBeAg) Seroconversion in HBeAg-Positive Children With a Normal Alanine Aminotransferase Level.

It is not clear whether baseline hepatitis B core antibody (anti-HBc) level in hepatitis B e antigen (HBeAg)-positive children with a normal alanine aminotransferase (ALT) level is predictive of spontaneous HBeAg seroconversion. We investigated the correlation between anti-HBc level and the natural course of chronic hepatitis B (CHB) virus (HBV) infection in children, particularly the ability of baseline anti-HBc level to predict spontaneous HBeAg seroconversion during long-term follow-up. HBeAg-positive children with untreated CHB and a normal ALT level were followed longitudinally. Anti-HBc level was determined by double-sandwich immunoassay. Effects of anti-HBc levels and other parameters on spontaneous HBeAg seroconversion and the natural course of CHB were assessed. A total of 182 children (106 males) with a median age at enrollment of 10.6years (interquartile range [IQR], 10.3-15.3) were followed for a median of 19.8years (IQR, 11.9-21.9). Spontaneous HBeAg seroconversion occurred in 85 children (46.7%) during the follow-up. A baseline anti-HBc titer of>500IU/mL (hazard ratio [HR] = 2.81), HBV genotype B and B+C (HR=3.46), and a baseline hepatitis B surface antigen titer of≤4.8 log10 IU/mL (HR=3.09) were predictive of spontaneous HBeAg seroconversion, based on multivariable survival analysis (P<0.001). In cases remaining HBeAg positive, their anti-HBc levels increased gradually during follow-up because of ongoing inflammation. Conclusion: Baseline anti-HBc level is predictive of spontaneous HBeAg seroconversion in HBeAg-positive children with a normal ALT level. Anti-HBc level reflects anti-HBV immune response in the HBeAg-positive normal ALT phase of CHB.

High mutation prevalence of precore and basal core promoter in pregnant women who underwent spontaneous HBeAg seroconversion within one year postpartum

BackgroundSeroconversion of hepatitis B e antigen (HBeAg) is a critical event in the natural course of hepatitis B virus (HBV) infection. AimWe herein characterize the virological factors associated with postpartum spontaneous HBeAg seroconversion. MethodsA total of 214 pregnant women positive for both hepatitis B surface antigen (HBsAg) and HBeAg were followed up at 7–12 months postpartum. ResultsOf the subjects, 26 (12.1%) achieved spontaneous HBeAg seroconversion. Receiver operating curve analysis indicated that HBV DNA level <1.0 × 107 IU/mL, HBsAg <1.0 × 104 IU/mL and HBeAg <7.36 × 102 S/CO each independently predicted HBeAg seroconversion within 12 months postpartum. At delivery, 73.1% (19/26) women with postpartum HBeAg seroconversion had precore (PC) and/or basal core promoter (BCP) mutations, higher than that (5/36, 13.9%) in the women without postpartum seroconversion. Binary logistic regression analysis indicated that the presence of mutations in PC, BCP, and both PC and BCP at delivery was associated with an increased likelihood (OR = 13.286, 16. 238, and 22.143 respectively, all P < 0.05) to undergo postpartum spontaneous HBeAg seroconversion. ConclusionThese results suggest that quantitative determination of virological markers and sequencing PC and BCP can predict spontaneous HBeAg seroconversion, which could be valuable in deciding antiviral therapy against HBV.

Antiviral therapy in hepatitis B virus-infected children with immune-tolerant characteristics: A pilot open-label randomized study

Chronic infection with hepatitis B virus (HBV) in children is a serious health problem worldwide. How to treat children with immune-tolerant chronic hepatitis B infection, commonly characterized by hepatitis B e antigen (HBeAg) positivity, high viral load, normal or mildly elevated alanine aminotransferase and no or minimal inflammation in liver histology, remains unresolved. This trial aims to study the benefits of antiviral therapy in children with these characteristics. This is a pilot open-label randomized controlled study. From May 2014 to April 2015, 69 treatment-naive chronically HBV-infected children, aged 1 to 16 years, who had immune-tolerant characteristics were recruited to this trial and randomly assigned, in a 2:1 ratio, to treatment group and control group. Patients in the treatment group received either interferon-α (IFN) monotherapy or consecutively received IFN monotherapy, combination therapy of IFN and lamivudine (LAM), and LAM therapy alone. All patients were observed until week 96. At baseline, epidemiological, biochemical, serological, virological and histological indices were consistent across the treatment and control groups. Of the 46 patients in the treatment group, 73.91% had undetectable serum HBV DNA, 32.61% achieved HBeAg seroconversion and 21.74% lost hepatitis B surface antigen (HBsAg) at the endpoint. No LAM resistance emerged at week 96. In the control group, only one (4.35%) patient underwent spontaneous HBeAg seroconversion and had undetectable serum HBV DNA during observation, and moreover, none developed HBsAg clearance. For all patients, no serious adverse events were observed. Antiviral treatment with a sequential combination of IFN and LAM resulted in a significant improvement in the rates of undetectable serum HBV DNA, HBeAg seroconversion and HBsAg loss in children with chronic HBV infection and immune-tolerant characteristics. There is a lack of data regarding treatment of immune-tolerant chronic hepatitis B (CHB). It remains unresolved how children with immune-tolerant CHB should be treated. This paper reports the outcomes from a pilot open-label randomized controlled trial on antiviral therapy in children with immune-tolerant characteristics. It shows that a sequential combination of interferon-α and lamivudine was beneficial.

Predictors of hepatitis B e antigen-negative hepatitis in chronic hepatitis B virus-infected patients from childhood to adulthood.

Hepatitis B e antigen (HBeAg)-negative hepatitis is a clinical indicator of poor outcome for chronic hepatitis B viral (HBV) infection. This long-term prospective cohort study aimed to elucidate the predictors of developing HBeAg-negative hepatitis in chronic HBV-infected subjects followed from childhood to adulthood. We followed 434 HBeAg-positive chronic HBV-infected patients from a median age of 7.22 years (interquartile range 4.31-10.21 years). Spontaneous HBeAg seroconversion occurred in 359 subjects at a median age of 13.93 years (interquartile range 8.76-20.59 years), and 75 subjects developed HBeAg seroconversion after antiviral therapy. These patients were followed for a median of 14.40 years (interquartile range 6.14-22.02 years) after HBeAg seroconversion. Clinical data were analyzed to delineate the predictors of developing HBeAg-negative hepatitis. The HBV basal core promoter and precore/core gene sequences were also evaluated in subjects with and without HBeAg-negative hepatitis. The overall annual incidence of HBeAg-negative hepatitis was 0.37% (95% confidence internal 0.35-0.39) in spontaneous HBeAg seroconverters. The overall annual incidence of HBeAg-negative hepatitis increased to 2.64% in lamivudine-treated subjects but did not increase in those treated with interferon-alpha (0.58%). Male gender (hazard ratio = 3.15), HBV genotype C (hazard ratio = 4.40), HBeAg seroconversion after 18 years of age (hazard ratio = 2.46), and lamivudine therapy prior to HBeAg seroconversion (hazard ratio = 1.42) were predictors of HBeAg-negative hepatitis in HBeAg seroconverters (P < 0.05). HBeAg-negative hepatitis subjects carried more A1762T/G1764A, C2063A, and A2131C HBV gene mutations than those without HBeAg-negative hepatitis. HBeAg seroconversion during childhood predicts a lower risk of HBeAg-negative hepatitis in later life. Interferon-alpha therapy may be an effective antiviral therapy beneficial in chronic HBV-infected children with severe inflammation that facilitates HBeAg seroconversion in earlier life.

Association between single-nucleotide polymorphisms and early spontaneous hepatitis B virus e antigen seroconversion in children.

BackgroundThe disease progression following hepatitis B virus (HBV) infection is associated with single-nucleotide polymorphisms (SNPs). However, the role of SNPs in chronic HBV infection in children remains unclear. Here, we investigate the association between SNPs and early spontaneous hepatitis B e antigen (HBeAg) seroconversion in children with chronic hepatitis B infection.MethodsThis was a retrospective cohort study. We genotyped seven SNPs in the following genes, interleukin (IL)-10 (rs1800871 and rs1800872), human leukocyte antigen (HLA)-DPA1 (rs3077), HLA-DPB1 (rs9277535), HLA-DQB2 (rs7453920), HLA-DQB1 (rs2856718), and IL28B (rs8099917), in patients with chronic HBV infection using PCR and sequencing. These variants were analyzed for an association with early HBeAg seroconversion in children.ResultsOf 225 Japanese patients with chronic hepatitis B virus infection (male/female: 105/120, median age at initial visit: 6 years; range 0–44 years), 52 achieved spontaneous HBeAg seroconversion at the age of 10 years or younger (G1: early seroconversion group), and 57 did not achieve spontaneous HBeAg seroconversion under the age of 20 years (G2: late or no seroconversion group). Of the seven SNPs, only the HLA-DPA1 SNP displayed a low p-value (P = 0.070), but not significant, to have early HBeAg seroconversion in the dominant model and in the allele model (P = 0.073) using the chi-square test. The association study found a low p-value, but not significant, to have early HBeAg seroconversion in the dominant model for HLA-DPA1 (genotype TC + TT vs. CC, P = 0.070, odds ratio: 2.016, 95% confidence interval: 0.940-4.323) using a logistic regression model.ConclusionAlthough the HLA-DPA1 SNP did not show a statistically significant association with early HBeAg seroconversion in this study, the HLA-DPA1 SNP might increase the likelihood of achieving early spontaneous HBeAg seroconversion in children.

Outcomes of Patients With Chronic Hepatitis B Who Do Not Meet Criteria for Antiviral Treatment at Presentation

The availability of potent, well-tolerated, oral antivirals with low rates of resistance has led many experts to recommend liberalizing indications for the treatment of chronic hepatitis B (CHB). This study sought to determine the rate of transitions to an active phase of infection, the frequency of treatment initiation, and the clinical outcomes of patients with CHB who did not meet treatment criteria at presentation. We reviewed medical records of patients with CHB, seen in the liver clinics at the University of Michigan Health System from 1999 through 2010, who did not receive antiviral treatment within 6 months of presentation. We collected data on transitions between different phases of CHB, hepatitis B e antigen (HBeAg) seroconversion, loss of hepatitis B surface antigen (HBsAg), and the development of hepatocellular carcinoma (HCC). Data analyses were censored or truncated at the time of treatment initiation or development of an outcome. Of the 234 patients analyzed, 52.1% were men (median age, 35 y), 72.2% were Asian, and 81.2% were HBeAg-negative. During a median follow-up period of 51 months, 19.2% of patients transitioned to a more active disease phase and 18.8% started antiviral therapy. Of the 44 HBeAg-positive patients, 4 patients (9%) had spontaneous HBeAg seroconversion. Nine HBeAg-negative patients but none of the HBeAg-positive patients lost HBsAg. The cumulative probability of HBsAg loss among HBeAg-negative patients was 1% at year 5 and 21% by year 10. No patients had flares of icteric hepatitis or hepatic decompensation. None of the HBeAg-positive patients developed HCC, whereas 2 HBeAg-negative patients developed HCC. Careful monitoring of patients with CHB who did not meet treatment criteria at presentation permits timely initiation of treatment, with a low risk of adverse clinical outcomes, based on a retrospective study with a median follow-up period of 4.3 years. These findings indicate that current guidelines for initiating treatment are appropriate.

Patients with interferon-induced HBeAg seroconversion have a higher risk of HBV reactivation and HBeAg seroreversion.

It remains unclear whether chronic hepatitis B patients who undergo interferon (IFN)-induced hepatitis B e antigen (HBeAg) seroconversion have a higher risk of hepatitis B virus (HBV) reactivation and HBeAg seroreversion than those with spontaneous HBeAg seroconversion. A total of 80 and 251 non-cirrhotic patients with interferon-induced and spontaneous HBeAg seroconversion, respectively, were analyzed. Compared to spontaneous HBeAg seroconverters, more IFN-induced HBeAg seroconverters were males (p=0.004). For all patients, the IFN-induced HBeAg seroconverters faced a higher risk of HBV reactivation and HBeAg seroreversion than spontaneous HBeAg seroconverters (p<0.001). For spontaneous HBeAg seroconverters, age at HBeAg seroconversion, male sex, HBV genotype C, and pre-S deletions were independent predictors of HBV reactivation. For IFN-induced HBeAg seroconverters, older age at baseline and HBV genotype C were independent predictors of HBV reactivation. To determine whether the difference in the rates of HBV reactivation or HBeAg seroreversion between two groups was age-dependent, patients were grouped and analyzed according to their age at HBeAg seroconversion (20-30, 31-39, ≥40years). IFNs treatment was an independent factor in HBV reactivation and HBeAg seroreversion only in the groups of patients 31-39 and ≥40years of age, but not in the group of patients 20-30years of age. IFN-induced rather than spontaneous HBeAg seroconversion was associated with higher risk of HBV reactivation and HBeAg seroreversion, especially in patients who were older than 30years at HBeAg seroconversion.

Hepatitis B surface antigen level complements viral load in predicting viral reactivation in spontaneous HBeAg seroconverters

The level of hepatitis B surface antigen (HBsAg) has been shown to complement hepatitis B virus (HBV)-DNA level in predicting disease progression in hepatitis B e antigen (HBeAg)-negative patients, especially those with low viral loads. Whether this finding could be seen in spontaneous HBeAg seroconverters remains unclear. A retrospective cohort of 390 Taiwanese spontaneous HBeAg seroconverters with a mean follow-up period of 7.4 years was enrolled. The relationships between HBV-DNA/HBsAg levels and HBeAg-negative hepatitis/active viral replication (HBV-DNA level ≥ 2000 IU/mL) were investigated. In the overall cohort, serum HBV-DNA level served as a better predictor for HBeAg-negative hepatitis compared with HBsAg level. However, in those with HBV-DNA level < 2000 IU/mL, a higher HBsAg level was associated with a higher risk of HBeAg-negative hepatitis (P = 0.015). Multivariate analysis showed the hazard ratio of HBsAg level ≥ 1000 IU/mL versus < 1000 IU/mL was 4.1 (95% confidence interval: 1.3-13.6). When using the end-point of active viral replication, HBsAg ≥ 1000 IU/mL remained as an independent risk factor, with a hazard ratio of 2.5 (95% confidence interval: 1.1-5.9). In spontaneous HBeAg seroconverters with HBV-DNA level < 2000 IU/mL, HBsAg level ≥ 1000 IU/mL is associated with increased risks of HBeAg-negative hepatitis and active viral replication. Combining HBV-DNA < 2000 IU/mL and HBsAg level < 1000 IU/mL may be used to define minimal viral activity.

Higher proportion of viral basal core promoter mutant increases the risk of liver cirrhosis in hepatitis B carriers

Background and objectivePrecore (PC) variant (G1896A) and basal core promoter (BCP) variant (A1762T/G1764A) of HBV are associated with risk of hepatocellular carcinoma in HBV carriers. However, little is known about...

The Impact of Hepatitis B Virus Precore/Core Gene Carboxyl Terminal Mutations on Viral Biosynthesis and the Host Immune Response

We aimed to elucidate the impact of hepatitis B virus (HBV) precore/core gene mutations on spontaneous hepatitis B e antigen (HBeAg) seroconversion, HBV biosynthesis, and the human immune responses in chronic HBV-infected patients. We analyzed the HBV precore/core gene sequences by cloning method in 33 chronic HBV-infected patients during the inflammatory phase before spontaneous HBeAg seroconversion. The impact of the most prevalent mutant on HBeAg biosynthesis was assessed by Western blotting and native agarose gel analysis in Huh7 cells, and the human immune responses were assessed by in vitro stimulation of CD3+ CD8+ T lymphocytes of chronic HBV-infected subjects. The P135Q and G1896A were the most prevalent mutants before HBeAg seroconversion, acting as markers of HBeAg seroconversion (hazard ratios = 2.75 and 4.50; P = .01 and <.001, respectively). The P135Q mutants displayed decreased HBeAg secretion and HBV capsid molecular weight, while showing increased 22 kD HBeAg proprotein accumulation in Huh7 cells. The P135Q mutant peptide induced less interferon-γ expression in CD3+ CD8+ T lymphocytes in HBeAg-negative subjects compared to the wild-type peptide (P = .03). The HBV P135Q mutant emergence during the inflammatory phase was associated with HBeAg seroconversion. It was associated with altered HBV capsid assembly, HBeAg biosynthesis, and reduced human immune responses following HBeAg seroconversion.

Role of serum dehydroepiandrosterone sulfate level on the clearance of chronic hepatitis B virus infection

The natural course of chronic hepatitis B virus (HBV) infection and relevant host factors remain unclear. This study aims to investigate the impact of dehydroepiandrosterone sulfate (DHEAS) on the clearance of chronic HBV infection. Two hundred and one hepatitis B e antigen (HBeAg)-positive chronic HBV-infected children (101 females) were recruited. Serum DHEAS levels were determined in all subjects at 15years of age. Serum alanine aminotransferase (ALT) levels, DHEAS levels, HBV seromarkers, genotypes, and viral loads were included for analysis. Subjects with serum DHEAS levels >3.6μmol/L at midpuberty had earlier HBeAg seroconversion (median age, 14.7 vs. 18.2years; HR, 1.9; P=0.03), and the impact persisted even after adjusting for gender, HBV genotype, peak ALT levels, and viral load. Subjects with DHEAS levels >3.6μmol/L at 15years of age had more HBV viral titers decrement from 15 to 20years of age (mean±SD, 3.5±2.5 vs. 1.2±2.2log10copies/mL; P=0.05) and shorter duration for HBeAg seroconversion than others (mean±SD, 5.6±4.4 vs. 9.2±4.9years; P=0.02). Higher serum DHEAS levels at 15years of age are also associated with greater hepatitis B surface antigen (HBsAg) titer decrement from 15 to 20years of age (correlation coefficient=0.45, P=0.04). Higher serum DHEAS levels at midpuberty predicts more HBV viral load and HBsAg titer decrement from midpuberty to young adulthood. Higher serum DHEAS levels at midpuberty also correlate with younger age of spontaneous HBeAg seroconversion in chronic genotype B and C HBV-infected patients.

Young Chronic Hepatitis B Patients With Nucleos(t)ide Analogue-induced Hepatitis B e Antigen Seroconversion Have a Higher Risk of HBV Reactivation

It is unclear whether hepatitis B e antigen (HBeAg) seroconversion induced by nucleos(t)ide analogues (NUC) has a prognosis that is similar to that of spontaneous HBeAg seroconversion. A total of 148 noncirrhotic NUC-induced HBeAg seroconverters were consecutively enrolled. A historical control of 407 noncirrhotic spontaneous HBeAg seroconverters was also recruited. We compared the rates of HBeAg seroreversion and HBV reactivation between these 2 cohorts. There were 1652.8 and 465.2 person-years of follow-up for spontaneous and NUC-induced HBeAg seroconverters, respectively. Compared with NUC-induced seroconverters, spontaneous seroconverters were younger when achieving HBeAg seroconversion. We thus compared these 2 cohorts according to their age at HBeAg seroconversion. In patients achieving HBeAg seroconversion before 30 years of age, NUC-induced seroconverters had a higher 2-year HBeAg seroreversion rate than spontaneous seroconverters (12.0% vs 2.9%; P = .004) and were at a higher risk of HBV reactivation (hazard ratio, 4.6; 95% confidence interval, 1.5-14.4). Using multivariate analysis, NUC-induced HBeAg seroconversion remained a risk factor of both endpoints in young HBeAg seroconverters. NUC-induced HBeAg seroconverters may not have durable response after stopping therapy. For patients achieving HBeAg seroconversion before 30 years of age, the risk of HBeAg seroreversion and HBV reactivation is higher in NUC-induced seroconverters than spontaneous HBeAg seroconverters.

Combining the HBsAg decline and HBV DNA levels predicts clinical outcomes in patients with spontaneous HBeAg seroconversion.

The aim was to investigate whether the quantitation of the hepatitis B surface antigen (HBsAg) and hepatitis B virus (HBV) DNA levels can predict HBV reactivation and advanced liver disease after spontaneous hepatitis B e antigen (HBeAg) seroconversion. A total of 121 patients who experienced spontaneous HBeAg seroconversion were included in this longitudinal study. Serial HBsAg and HBV DNA levels were measured before and after HBeAg seroconversion. Of the 121 patients, 32 experienced HBV reactivation and six achieved an HBsAg loss after HBeAg seroconversion during the follow-up period. The decline in the HBsAg level was considerably more pronounced in patients without HBV reactivation when compared to those with HBV reactivation (p=0.016). Multivariate analysis revealed that the age of >40years at HBeAg seroconversion, male sex, and HBsAg decline, and HBV DNA levels at month 12 after HBeAg seroconversion were independent factors for the development of HBeAg-negative hepatitis. All the six patients who achieved HBsAg loss had HBsAg level of <1,000IU/mL at month 12 after HBeAg seroconversion (p<0.001). The risk of HBeAg-negative hepatitis, cirrhosis, and HCC was substantially increased in patients who had a combination of both, i.e., no decline in the HBsAg level and HBV DNA level of >10(4)copies/mL at month 12 after HBeAg seroconversion. Combining HBsAg reduction and HBV DNA levels at month 12 after HBeAg seroconversion was a useful marker to predict clinical outcomes in spontaneous HBeAg seroconverters. HBsAg level of <1,000IU/mL at month 12 after HBeAg seroconversion could predict the HBsAg loss after HBeAg seroconversion.

Combination and evolution of HBV mutant strains in the HBeAg-positive status predict clinical outcomes after HBeAg seroconversion.

We investigated whether the combined presence and evolution of hepatitis B virus (HBV) mutant strains in the hepatitis B e antigen (HBeAg)-positive status can predict clinical outcomes after HBeAg seroconversion. One hundred and eighty-six patients with spontaneous HBeAg seroconversion were enrolled into this longitudinal study. The sequences of pre-S, core promoter, and precore regions were determined at study entry and at the visit immediately before HBeAg seroconversion. Age ≥40years at HBeAg seroconversion, male sex, and higher HBV DNA levels at entry were independent predictors for HBeAg-negative chronic hepatitis B (CHB). Patients with combined mutations of pre-S deletions and T1762/A1764 had a significantly increased risk of cirrhosis and hepatocellular carcinoma (HCC) compared to patients with the wild type at both genomic regions. Combinations of pre-S deletions and T1762/A1764 were found on the same HBV genome by cloning analysis of full-length HBV genomes. Patients with a persistent presence of pre-S deletions and T1762/A1764 mutations, and new development of pre-S deletions in the HBeAg-positive status were significantly at an increased risk of HBeAg-negative CHB, cirrhosis, and HCC after HBeAg seroconversion than those with a persistent presence of the wild type at both genomic regions. After adjusting the other risk factors, the evolution of pre-S deletions was an independent predictor for cirrhosis [hazard ratio (HR): 1.52, 95% confidence interval (CI) 1.02-2.25] and HCC (HR: 4.0, 95% CI 1.6-10.1). The combined presence and evolution of pre-S deletions and T1762/A1764 in the HBeAg-positive status was a useful factor significantly predictive of clinical outcomes in patients with spontaneous HBeAg seroconversion.

Predictive effect of serial serum alanine aminotransferase levels on spontaneous HBeAg seroconversion in chronic genotype B and C HBV-infected children.

The present study aimed to investigate the association between serial serum alanine aminotransferase (ALT) and spontaneous hepatitis B e antigen (HBeAg) seroconversion age in chronic hepatitis B virus (HBV)-infected children. One hundred four HBeAg-positive chronic genotype B or C HBV-infected patients were included in this long-term prospective cohort study (mean initial age 7.20 years). Serial serum ALT levels and HBV serology markers were measured every 6 to 12 months. The 104 subjects made a total of 2525 visits during the study period, and the majority (93.6%) of visits were within a 1-year interval apart from previous visits. Cox proportional hazards model with time-dependent covariates was used in the survival analysis of HBeAg in these subjects. During the chronic course of HBV infection, the median remaining times to spontaneous HBeAg seroconversion were 8.35, 5.14, 4.25, 3.95, and 2.80 years after the ALT levels crossed 20, 30, 40, 60, and 150 IU/L, respectively. The incidence rate of spontaneous HBeAg seroconversion within 6 months when a subject entered the phase of ALT between 60 and 150 IU/L was 5.57 times that of the phase with ALT < 60 IU/L. The incidence rate of HBeAg seroconversion once ALT levels were above 150 IU/L was 9.87 times that of the phase of ALT < 60 IU/L. The ALT levels above 30 IU/L served as a cutoff of the inflammatory phase in chronic genotype B and C HBV-infected patients. Serial ALT levels in chronic HBV-infected subjects offer a predicted effect on the occurrence of spontaneous HBeAg seroconversion.

Management of Chronic Hepatitis B e Antigen-Negative Disease: Another Step Forward

Chronic hepatitis B (CHB) infection is a global health problem affecting more than 2 billion people worldwide. Among them, more than 75% reside in AsiaPacific countries. Although only a minority (15%–40%) of infected individuals go on to develop cirrhosis, liver failure, and hepatocellular carcinoma (HCC), which account for an estimated 0.5–1.2 million deaths per year, CHB is ranked as the 10th leading cause of death worldwide [ 1 ]. In Asia, most patients acquire hepatitis B virus (HBV) infection either during the perinatal period or in early childhood. In general, the natural course of chronic HBV infection consists of 4 phases, although not all patients go through all phases [ 2 ]. The initial immune-tolerant phase is characterized by the presence of hepatitis B e antigen (HBeAg), high serum HBV DNA levels, and persistently normal levels of alanine aminotransferase (ALT). Most patients in the immune tolerant phase have minimal liver injury, and prognosis is favorable during follow-up of up to 10 years. There is usually no, or only minimal, disease progression while serum ALT concentrations remain normal [ 3 , 4 ]. This is followed by an immune clearance phase when the HBeAg-positive patients have raised ALT levels. During this phase, spontaneous HBeAg seroconversion occurs at a rate of 10%–20% per year. HBeAg seroconversion is frequently, but not always, accompanied by a sudden increase in ALT levels [ 5 ]. Patients who undergo spontaneous HBeAg seroconversion before the age of 40 have a good prognosis [ 6 ]. They then enter an inactive (carrier) phase, which is characterized by the absence of HBeAg, the presence of HBe antibody (anti-HBe), persistently normal ALT levels, and low or undetectable levels of serum HBV DNA. Patients in this phase have a favorable prognosis [ 7 ]. Recently, because of aging populations and increased availability of molecular technology, more patients in Asia are being noted to enter the 4th reactivation phase. This phase, also termed HBeAg-negative CHB, is characterized by the absence of HBeAg, the presence of anti-HBe, intermittently or persistently elevated serum HBV DNA and ALT levels, and active inflammation in the liver. The annual rates of reactivation of hepatitis B are 1.5%–3.3%, and these individuals usually have more advanced liver disease than patients in the other phases of the disease. Indeed, it is estimated that subjects with HBeAg-negative hepatitis developed cirrhosis, with or without HCC, at a rate of 3%–4% per year. Currently, 7 treatments are approved for CHB e antigen–negative patients, including 2 formulations of interferon (IFN; conventional IFN and PEG-IFN) and 5 nucleoside/nucleotide analogs (lamivudine, adefovir dipivoxil, entecavir, telbivudine, and tenofovir disoproxil). The use of these therapeutic agents results in varying success. Viral relapse occurs in almost all patients when nucleoside/nucleotide analogs are discontinued, and a 1-year course of PEGIFN resulted in undetectable serum HBV DNA and normalization of ALT levels in fewer than one-third of patients. Learning from chronic hepatitis C virus infection,